EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma.

Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE: BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

Evaluation of a semi-automated approach for FDG PET image analysis for routine clinical application in patients with multiple myeloma.

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

A novel collagenase from Vibrio Alginolyticus: experimental study for Dupuytren's disease.

OBJECTIVE: Dupuytren contracture (DC) is a highly prevalent hand affection in which contracted fingers compromise hand function. It is a benign fibroproliferative condition affecting the hand palmar fascia with a deposition of excess matrix proteins in the extracellular space of the palmar aponeurosis. In particular type III over type I collagen V. Alginolyticus collagenase (CVA), is a new enzyme that is fully active on the collagen filaments and inactive on other components of the dermal extracellular matrix. The aim of this study is to evaluate the safety and effectiveness of an intra-lesional injection of CVA on an animal model of subcutaneous fibrosis mimicking the pathological anatomy of the cord of Dupuytren's disease. MATERIALS AND METHODS: We performed an in vivo study on 27 rats that were randomized into four groups, and we evaluated macroscopic and microscopic analysis examining the inflamed cell population and the extracellular matrix. RESULTS: In all cases, no skin necrosis, skin tears or wound dehiscence were recorded, demonstrating the safety of the CVA in contrast to group D which had full-thickness skin necrosis, and this is confirmed by the microscopic analysis of the samples treated with CVA, where no hematomas are found around the fibrotic area with the absence of leukocyte infiltrates and macrophages. CONCLUSIONS: CVA is confirmed to be selective for collagens I and III, reducing the risk of vascular lesions or skin ulcerations.

Norfloxacin prophylaxis effect on multidrug resistance in patients with cirrhosis and bacterial infections.

It is unclear whether norfloxacin predisposes to infections by multidrug-resistant organisms (MDROs). We aimed to evaluate if patients with cirrhosis receiving norfloxacin prophylaxis at the time of the diagnosis of bacterial infections were more likely to present a multidrug-resistant isolate than those without prophylaxis. This is a cross-sectional study of hospitalized patients with cirrhosis and bacterial infections from Argentina and Uruguay (NCT03919032) from September 2018 to December 2020. The outcome variable was a multidrug-resistant bacterial infection. We used inverse probability of treatment weighting to estimate the odds ratio (OR) of norfloxacin on infection caused by MDROs considering potential confounders. Among the 472 patients from 28 centers, 53 (11%) were receiving norfloxacin at the time of the bacterial infection. Patients receiving norfloxacin had higher MELD-sodium, were more likely to have ascites or encephalopathy, to receive rifaximin, beta-blockers, and proton-pump inhibitors, to have a nosocomial or health-care-associated infection, prior bacterial infections, admissions to critical care units or invasive procedures, and to be admitted in a liver transplant center. In addition, we found that 13 (24.5%) patients with norfloxacin and 90 (21.5%) of those not receiving it presented infections caused by MDROs (adjusted OR 1.55; 95% CI: 0.60-4.03; p = 0.360). The use of norfloxacin prophylaxis at the time of the diagnosis of bacterial infections was not associated with multidrug resistance. These results help empiric antibiotic selection and reassure the current indication of norfloxacin prophylaxis in well-selected patients.Study registration number: NCT03919032.

A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Neotropical Studies on Hymenochaetaceae: Unveiling the Diversity and Endemicity of Phellinotus.

Phellinotus, a neotropical genus of wood-decay fungi commonly found on living members of the Fabaceae family, was initially described as containing two species, P. neoaridus and P. piptadeniae. The members of this genus, along with six other well-established genera and some unresolved lineages, are the current representatives of the 'phellinotus clade'. On the other hand, based on a two-loci phylogenetic analysis, some entities/lineages of the 'phellinotus clade' have been found in Fomitiporella s.l. In this work, we performed four-loci phylogenetic analyses and based on our results the genera of the 'phellinotus clade' are shown to be monophyletic groups. In addition to the natural groups confirmed as different genera, morphological revisions, phylogenetic relationships, and host distribution of different specimens resembling P. neoaridus and P. piptadeniae revealed three new species in the Phellinotus genus, referred to here as P. magnoporatus, P. teixeirae and P. xerophyticus. Furthermore, for P. piptadeniae a narrower species concept was adopted with redefined morphological characters and a more limited distribution range. Both P. neoaridus and P. teixeirae have a distribution range restricted to seasonally dry tropical forests in South America. Additionally, based on detailed morphological revisions Phellinus badius, Phellinus resinaceus, and Phellinus scaber are transferred to the Phellinotus genus. The geographic distribution and host range of the genus are then discussed.

Conversion of fruit waste-derived biomass to highly microporous activated carbon for enhanced CO2 capture.

Activated carbons were prepared from different Amazonian fruit waste-derived biomass residues from the Amazon to store CO2 at low pressure. The samples were carbonized in under flowing N2 flow atmosphere and activated with KOH. The carbon materials obtained were physically and structurally characterized by the analysis of N2 isotherms for textural characterization, X-ray fluorescence (XRF), ash content, X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), and applied for CO2 adsorption. Temperature programmed desorption (TPD), the isosteric heat were also calculated. The values of the specific surface area (SBET) ranged from 1824 to 2004 m2/g, and the total pore volume varied between 0.68 and 0.79 cm3/g. These results confirm that the obtained activated carbons are microporous materials. The highest CO2 adsorption under the pressure of 1 bar was achieved in activated carbon derived from andiroba seeds ANKO1, the adsorption of carbon dioxide at 1 bar was being 7.18 and 4.81 mmol/g at 273 K and 298 K, respectively. As a result, the most important factor in the preparation of activated carbon for CO2 capture is primarily rich in extremely the high amount of small micropores.

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Venetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM. PATIENTS AND METHODS: This phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy. RESULTS: Eight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months. CONCLUSIONS: Given the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Skeletal muscle repair in a rat muscle injury model: the role of growth hormone (GH) injection.

OBJECTIVE: Muscle injury tends to heal with incomplete functional recovery. Among the growth factors released in the physio-pathological response of muscle lesion, the Insulin-like Growth-Factor-1 (IGF-1) results in an engine factor of the reparation program. The therapeutic use of growth factors has been exploited to improve healing. As IGF-1 is a primary mediator of the effects of growth hormone (GH), we exploited its systemic administration to muscle recovery in a rat model of muscle injury. MATERIALS AND METHODS: Monolateral lesion of the longissimus dorsi muscle of rats was performed. Animals were divided into 5 groups: four groups for histological studies and serum hormone dosage, whilst the fifth group represented the uninjured control. Rat GH was intraperitoneally administered after 24h from the surgical lesion at three different concentrations (0.1, 0.2, 0.4 mg/kg). At 3 days from surgery, immunohistochemical and histological analyses evaluated the expression of MyoD and Myogenin, and the presence of neovascularization and inflammation, respectively. After 2 months, we analyzed the presence of muscle regeneration and fibrosis. RESULTS: The treatment with GH resulted in a significant increase in neovascularization and Myogenin expression at 24h from injury in comparison with the control. This suggested speed up biological recovery times. After two-months, a dose-dependent increase of the connective component was observed. CONCLUSIONS: The potential effect of GH on muscle repair and regeneration, through the activation of satellite cells already demonstrated in vitro, was confirmed in this in vivo experimental approach. This study sheds light on the role of growth factors in damage repair mechanisms to find an appropriate biological treatment for muscle injury.

Metachronous occurrence of anal melanoma and papillary thyroid carcinoma in a 72-year-old female: Case in images

@#Anal melanoma is a rare melanocytic malignancy, which roughly comprises 2% of all anorectal malignancies.1 2 The anal area is the most common site for primary gastrointestinal melanomas.2 Patients with anal melanomas commonly complain of bleeding, anal pain and mass, tenesmus, and changes in bowel habits. In cases with metastases, symptoms such as weight loss, anemia, fatigue and bowel obstruction could be present.2 Risk factors of anal melanoma include old age, multiple sexual partners, anal sex, smoking, history of other malignancies (i.e., cervical, vulvar, or vaginal cancer), activation of the receptor tyrosine kinase c-Kit, and family history of malignancies.3 4 The diagnosis of anal melanoma is established through biopsy—usually done with colonoscopy—and immunological staining.5 HMB-45 is the immunological stain commonly used for the detection of both primary and metastatic melanomas.6 Endoscopic ultrasonography also helps to characterize lesions and assess the depth of infiltration.7

Postoperative outcomes of patients with severe obesity who underwent laparoscopic sleeve gastrectomy: Case series

@#Globally, especially in the Asian and African regions, there has been a rising burden of obesity due to high consumption of energy-dense foods and the increase of physical inactivity caused by urbanization and sedentary lifestyle changes.1 Bariatric surgery, or weight-loss surgery, remains to be the most effective treatment for morbid obesity, and it also has resulted in a substantial improvement of obesity-related comorbidities, especially type 2 diabetes mellitus.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.

INTRODUCTION: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. METHODS: A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS: No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Combination of Coenzyme Q10 Intake and Moderate Physical Activity Counteracts Mitochondrial Dysfunctions in a SAMP8 Mouse Model.

Aging skeletal muscles are characterized by a progressive decline in muscle mass and muscular strength. Such muscular dysfunctions are usually associated with structural and functional alterations of skeletal muscle mitochondria. The senescence-accelerated mouse-prone 8 (SAMP8) model, characterized by premature aging and high degree of oxidative stress, was used to investigate whether a combined intervention with mild physical exercise and ubiquinol supplementation was able to improve mitochondrial function and preserve skeletal muscle health during aging. 5-month-old SAMP8 mice, in a presarcopenia phase, have been randomly divided into 4 groups (n = 10): untreated controls and mice treated for two months with either physical exercise (0.5 km/h, on a 5% inclination, for 30 min, 5/7 days per week), ubiquinol 10 (500 mg/kg/day), or a combination of exercise and ubiquinol. Two months of physical exercise significantly increased mitochondrial damage in the muscles of exercised mice when compared to controls. On the contrary, ubiquinol and physical exercise combination significantly improved the overall status of the skeletal muscle, preserving mitochondrial ultrastructure and limiting mitochondrial depolarization induced by physical exercise alone. Accordingly, combination treatment while promoting mitochondrial biogenesis lowered autophagy and caspase 3-dependent apoptosis. In conclusion, the present study shows that ubiquinol supplementation counteracts the deleterious effects of physical exercise-derived ROS improving mitochondrial functionality in an oxidative stress model, such as SAMP8 in the presarcopenia phase.

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.

INTRODUCTION: Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. METHODS: In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. RESULTS: Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. CONCLUSIONS: The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. FUNDING: AbbVie in collaboration with Genentech/Roche.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.

Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 µg/mL, 12.6 ± 5.4 µg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.

Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin.

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate. 2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100  mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study. 3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (Cmax) by 35% and area under the plasma-concentration time curve (AUC0-∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Neupsilin-Inf em um modelo de avaliação neuropsicológica breve para centros de saúde / Neupsilin-Inf in a model of brief neuropsychological assesment for health centers / Neupsilin-Inf en un modelo de evaluación neuropsicológica breve para centros de salud

Este estudo teve como objetivo analisar o uso do NEUPSILIN-Inf num modelo de avaliação neuropsicológica breve em crianças atendidas em um serviço assistencial. As etapas seguidas no modelo de avaliação neuropsicológica breve são: sala de espera, grupo de crianças e avaliação neuropsicológica individual. A análise da aplicabilidade do NEUPSILIN-Inf na detecção de déficits cognitivos foi realizada comparando o desempenho de 171 crianças com possíveis transtornos do neurodesenvolvimento a 358 crianças da amostra de normatização, tendo a média marginal do escore ajustado pela idade. Em todas as tarefas do NEUPSILIN-Inf, o grupo clínico mostrou desempenho inferior. O conjunto de dados do modelo de avaliação pode gerar hipóteses diagnósticas, como deficiência intelectual, possíveis quadros de transtornos da aprendizagem ou específicos de linguagem. Frente à alta escassez de atendimento público para crianças com possíveis transtornos do neurodesenvolvimento, este pode ser um modelo economicamente eficiente para centros de saúde em diversas regiões do Brasil. (AU)

This study aimed to analyze the use of NEUPSILIN-Inf in a model of brief neuropsychological assessment for children attending a helthcare service. The steps followed in the brief neuropsychological assessment model are waiting room, children's group, and individual assessment. The analysis of this model's efficacy in detecting cognitive deficits through NEUPSILIN-Inf was conducted by comparing the performance of 171 children with possible developmental disorders to 358 children from the normative sample of NEUPSILIN-Inf. The clinical group showed lower performance in all NEUPSILIN-Inf 's tasks. The set of data derived from the evaluation model can underlie diagnostic hypotheses, such as intellectual disabilities, learning disorders or specific language impairment. Taking into account the restrictive public care for children with possible developmental disorders, this model can be considered a cost-effective possibility to be accomplished by health centers in different Brazilian regions. (AU)

Este estudio tuvo como objetivo analizar el uso de NEUPSILIN-Inf como un modelo de evaluación neuropsicológica breve para niños, atendidos en un servicio de asistencia pública. Las etapas seguidas para evaluación neuropsicológica breve fueron: sala de espera, grupo de niños, evaluación neuropsicológica individual. El análisis de aplicabilidad NEUPSILIN-Inf para detectar déficits cognitivos, fue realizado comparando el rendimiento de 171 niños con posibles trastornos de neuro-desarrollo y 358 niños de la muestra de normalización, obteniendo la media marginal del resultado, ajustado por la edad. En todas las tareas del NEUPSILIN-Inf, el grupo clínico tuvo un rendimiento inferior. El conjunto de datos del modelo de evaluación puede generar hipótesis diagnósticas, como deficiencia intelectual, posibles trastornos de aprendizaje o específicos de lenguaje. Ante la escasez de atendimiento público para niños con posibles trastornos de neurodesarrollo, este modelo puede ser eficiente desde el punto de vista económico en centros de salud en varias regiones de Brasil. (AU)